Because HIV-1 only establishes infections in humans and chimpanzees and only induces disease in humans, SIV/HIV chimeric viruses (SHIVs) have been constructed to examine the pathogenicity and develop vaccines pertaining to HIV-1 encoded proteins in the more tractable Asian macaque model system. We have reported that SHIV(DH12) replicates to high titers, induces p27 antigenemia, and induces immunodeficiency in pig-tailed macaques. However, in SHIV(DH12) infected rhesus monkeys, virus loads are consistently 100-fold lower, plasma p27 is undetectable, and none of the inoculated animals have ever developed CD4+ T lymphocyte depletion or signs of disease. We previously reported that the administration of anti-human CD8 MAb to rhesus macaques at the time of primary SHIV(DH12) infection, resulted in marked elevations of virus loads. One of the treated animals experienced rapid and profound depletions of circulating CD4+ T lymphocytes. Although the CD4+ T cell number partially recovered, this monkey subsequently suffered significant weight loss and was euthanized. A tissue culture virus stock derived from this animal, designated SHIV(DH12R), induced marked and rapid CD4+ cell loss following intravenous inoculation of rhesus monkeys. Retrospective analyses of clinical specimens, collected during the emergence of SHIV(DH12R) indicated: 1) the input cloned SHIV remained the predominant virus during the first 5 to 7 months of infection; 2) variants bearing only a few of the SHIV(DH12R) consensus changes first appeared 7 months following the administration of anti-CD8 MAb; 3) high titers of neutralizing antibody directed against the input SHIV were detected by week 10 and persisted throughout the infection; 4) no neutralizing antibody against SHIV(DH12R) ever developed.